3-179198826-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006218.4(PIK3CA):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PIK3CA NM_006218.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.88

Genes affected

PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.1A>G	p.Met1?	start_lost	2/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.1A>G	p.Met1?	start_lost	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.1A>G	p.Met1?	start_lost	2/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360626 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 671068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.43e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermal nevus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 25, 2018

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS1. -

Cowden syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2019

This variant has not been reported in the literature in individuals with PIK3CA-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PIK3CA cause disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the PIK3CA mRNA. The next in-frame methionine is located at codon 16. -

Megalencephaly-capillary malformation-polymicrogyria syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 09, 2023

Criteria applied: PVS1_MOD,PS2_MOD,PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-3.6	D;N;.;N
REVEL	Pathogenic	0.70
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		0.27	.;B;.;.
Vest4		0.88
MutPred		0.96		Loss of glycosylation at P2 (P = 0.1746);Loss of glycosylation at P2 (P = 0.1746);Loss of glycosylation at P2 (P = 0.1746);Loss of glycosylation at P2 (P = 0.1746);
MVP		0.96
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1724332515; hg19: chr3-178916614; COSMIC: COSV55935970;